Abstract

3908

Since 1984 we followed 15.396 women in the DOM breast cancer screening cohort who provided individual data on their suffering -at ages ranging from 2 to 33 years- from the Dutch Famine that lasted from november 1944 until may 1945. Having been exposed shifted several known breast cancer risk factors in a ’preventive’ direction, (adult height by shortening leg-length, postponement of menarche, and advancement of the menopause). However the amount of breast dysplasia (DY) showed opposite effects depending on the ages at exposure; whereby pre-pubertal age at exposure turned out to be the most vulnerable time-window. Similarly famine exposure moved the set-points of sex-hormone and IGF to higher levels in those severely exposed. Breast cancer itself INCREASED (OR 1.48 95%CI 1.09 –2.01) in heavily exposed women. Excluding breast cancer, no clear protective effect on other tumors was found. The overall mortality until 1996 seemed unaffected by exposure to the Famine. As opposed to cancer reducing and life extending effects of caloric deprivation reported in rodent studies, often based on lifelong feeding schemes, we found that in humans short term severe caloric restriction in youth caused a dissociation between effects on risk factors and effects on the final outcome, with effects in opposite directions, reducing the levels of risk factors while increasing actual breast cancer risk itself. Such lasting effects seemed limited to breast cancer. Pregnancies turned out to have an overriding (protective) impact as effects on breast cancer were mainly limited to nulliparous women. To explain these unexpected results we propose a hypothesis that focusses on the roles mitochondria play in reproductive development and cellular surveillance, as mitochondria determine 1. The cellular energy/ATP provision and related free radical spill from OXPHOS. 2. The synthesis of cholesterol and initial step of sex-steroid (pregnenolol) production. 3. The execution of apoptosis, contributing to both the development and involution of the breasts and the removal of (pre)-cancerous cells.